The Body Covers: The XIII International AIDS Conference
Plenary Session: Living with AIDS
July 11, 2000
Viral factors in HIV disease (TuOr35)Adding his voice to many of those at this conference, Dr. Ho started just with a picture of HIV. He stated simply that this is the cause of AIDS. He implored the President of South Africa Mbeki to acknowledge the work that must be done given that HIV has clearly been shown to be the problem. Ho asked Mbeki to no longer postpone taking actions to both prevent and treat HIV infection in this country.
Ho's work has been based on monitoring the growth of HIV, noting that when untreated, there is a viral set point. Antivirals decrease HIV's growth. It has been clearly shown that initially there is a rapid drop in the viral load, followed by a slower negative slope of viral load. These two rates in the drop of viral load reflects the work that shows that there are two types of cells actively producing HIV on a daily basis. The rapid initial drop occurs because of shutting down production in the CD4 cells. These cells live on average just one day after infection by HIV. Once HIV is released and is outside of a cell, HIV lives on average only 30 minutes, and in that time must quickly enter new uninfected cells to continue its growth. As a result, on average, when someone is off treatment, over one billion viral particles are produced daily.
Given the error rate of this virus when it replicates, it is likely that a virus with a mutation in each of its gene base pairs occurs each day. In addition, some dual combinations of mutations occur as well. It is this simple fact that has led to the necessity for multiple drugs being used, since some of these mutations will help the virus grow despite the antivirals used. Thus, even in someone not on treatment, there is likely to be at least some HIV that should be resistant to every single drug, if this drug were to be used one at a time. Fortunately, mutations conferring resistance to more than two medications in someone untreated is very rare, and this has led to the widespread use of triple-drug therapy to maintain suppression. In addition, if growth can be shut off, no new mutations should occur -- allowing triple-drug therapy to maintain its potency.
In addition to T4 cells, there are also other cells that live much longer than CD4 cells -- such as macrophages as well as other cell types -- and this accounts for the barrier to eradication of HIV from the body. Since the CD4 cell dies off quickly after infection, it is not the problem once HIV has been stopped. These longer-lived cells are the source of new replication when antivirals are stopped. Because these cells are so long-lived, despite current regimens, eradication of HIV from the body would take as long as 60 years of continued antiviral use. This prediction is based on the assumption that during this time, HIV growth is stopped, since any new growth of HIV would continue to increase the number of these long-lived cells.
Unfortunately, there are data showing that despite current antiviral drug pressure, there is continued regrowth of HIV -- at least in some people. Using a standard three- or four-drug combination, and establishing a viral load below detection, studies have shown that there can be some growth as shown by the evolution of the genetic material of HIV. This could only occur with ongoing replication at a low level. Therefore, despite the continued success of antivirals, at least some people will still have some very low level of HIV replication. In addition, lymph node biopsies demonstrate the presence of HIV particles at a low level. This escape from the antivirals continues the replenishment of the reservoir of infected cells in the body. However, there is evidence of decay of the reservoir -- in at least some individuals -- suggesting that eradication is still not impossible, although it would take either more potent combinations or ways of increasing the rate of death of infected cells.
Why does the virus grow despite drug pressure? These studies are done in those who are considered successful in terms of the response to antivirals, maintaining a viral load below 50 copies during the time on medication. As a result of maintaining this level, there is no evidence of drug resistance in these viruses. So how could HIV grow if it is below detection on our tests and not showing drug resistance? What is clear is that, when using more sensitive viral load tests, there is often evidence of HIV growing at a very low level but that this level does not lead to drug resistance. There is no clear answer still as to how this occurs. One potential explanation is cellular resistance which pumps the antiviral drugs out of the cells, allowing HIV to grow in the absence of drugs. Cellular pumps, called p-glycoprotein and others, might pump enough drug out of the cell to allow this finding to occur, since there would be viral growth without medications present, and this could allow growth without drug resistance.
Ho ended his talk noting that drugs that act on the outside of cells, such as fusion inhibitors, might be one important answer to this problem as these would not be influenced by such cellular pumps. Fusion inhibitors therefore could help further stop the growth of HIV infection. This new class of antivirals is now in development. They might both increase the potential to perhaps eradicate HIV from the body some day, as well as prolong the efficacy of any treatment strategy. By using a class of medications not influenced by cellular pumps, they could plug one potential gap in the medication "window" that HIV might be exploiting to grow despite antivirals.
Very early in HIV infection, and even when someone is treated during acute infection, a latent reservoir is generated that persists despite our best attempts to prevent it from forming. In addition, as just discussed by Dr. Ho, there is some persistent viral growth despite suppressing HIV replication to below the limits of detection on current assays of blood. This growth occurs in the environment of the lymph tissue. Antiviral therapy prevents the spread of HIV from cell to cell, but cells can continue to be a source of new HIV when viral growth is stimulated by various cell messenger proteins called cytokines. There are many such cytokines that stimulate viral growth, for example interleukin-2 (IL-2), and tumor necrosis factor (TNF). However, it is also noted that once a cell is used by HIV to produce more virus, that cell dies. Thus, recent work has used IL-2 to stimulate these latently infected cells to grow and express the HIV inside them, which results in the death of these cells. This was done in an attempt to "flush" HIV out of the reservoirs, or accelerate the rate that HIV-containing cells would express HIV and then die off. The hope here was to increase the likelihood of eradication, or at least decrease the importance of the reservoir by decreasing its size.
Last year, six patients who were on IL-2 for a few years were studied intensively. Three of them had very low levels of virus, such that no replication-competent HIV could be detected. The reservoir had been significantly reduced by IL-2 and drug pressure. These patients underwent a drug interruption. There unfortunately was a prompt return of HIV in all of these patients. Even the two patients with no detectable reservoir showed a rapid return of HIV with a similar rate of return of HIV when medications were stopped. However, when therapy was restarted, all the patients were able to reestablish suppression. Therefore, if eradication appears increasingly impossible, what new approaches could be tried to control HIV for the long term?
Prolonged courses of continuous antiviral therapy are becoming less desirable for many patients. The reasons include short- and long-term toxicity, including metabolic toxicities such as lipodystrophy or increases in blood lipids. In addition, the cost of these medications is a significant factor in many countries around the world and is a barrier to their use -- especially if therapy requires daily use. However, if therapy was intermittent, what could be accomplished? One approach has been to interrupt therapy as a way to stimulate the person's immune system and, by this "autovaccination" approach, alter the set point by stimulating immune defenses. At this time, the data suggest that this might be successful primarily in patients who are treated during acute HIV infection, and perhaps in a minority of patients who are treated during the chronic HIV infection phase. However, with regular drug-free periods, we can decrease toxicity and decrease cost while maintaining the benefits without creating drug resistance.
When medications were stopped in the IL-2 study mentioned above, by the end of one month off meds, the virus was returning in everyone. This return of growth occurs over the first few weeks (although during the first week there is a very slow return of HIV). Thus, Dr. Fauci's group, under the clinical leadership of Dr. Mark Dybul, is doing two studies. These medication interruption studies can only be safely done for patients with a viral load <50, as interruptions before that time can increase the risk of developing resistant virus. They are now testing two approaches to cycling therapy. One approach is to offer those with a viral load below 50 copies to then undergo cycles of two months on therapy, and then one month off HAART. While the results will be formally presented later in the week, Dr. Fauci presented a few slides of data from these studies.
At this time, there are only a few patients who have been studied with these approaches. One interesting observation is that while there can be a worrisome CD4 count drop after the first interruption, they are not seeing CD4 drops on subsequent interruptions. In almost all patients, treatment is effective when restarted, getting the viral load back down to <50. During the interruption, it is observed that at least some patients will have an augmentation of HIV-specific CD8 cells. Thus, after the rebound and restart on antivirals, there may be a lingering immune response after antivirals are started that may help delay the rebound on subsequent cycles. Will this permanently reestablish a new set point? Dr. Fauci does not anticipate that enough patients will establish a robust enough CD8 response to permanently control HIV without medications. However, during a short time off, these cells might slow the rebound of HIV, which would allow periods of time off of medication with less of a rebound of HIV when off those medications. Ultimately, even if we do not alter the set point, the periods of time off of medication might also allow recovery from toxicity, with minimal impact on the CD4 count from whatever rebound may occur. As if there is a drop in the CD4 count, these cells appear to come back once antivirals are restarted.
While exciting, there are a few extremely important cautions here. First, we must have data on the likelihood of resistance with this approach. If interruptions are done when the viral load is <50, there should be little risk of resistance when HIV does grow back. However, there is some concern, particularly when using drugs that stay in the body for several days, which is more a worry for the non-nucleosides and perhaps the dual protease inhibitor strategies now in common use. Thus, this approach must only be done in patients whose virus is not currently growing, as interruptions from therapy in patients with detectable viral growth increases the risk of creating drug-resistant HIV and threatening the response to medications once they are restarted. Second, we need information on how often the CD4 counts drop during treatment interruptions, and how reversible this drop is. Third, we know nothing about which interruption schedule will help to reverse drug toxicity while maintaining the benefits. Finally, it is noted that these approaches accept defeat in the battle to ultimately eradicate HIV from the body. These issues will be the focus of studies over the next years to better clarify how this approach might be successful in the long-term use of antivirals.
Concerning the question of when to start antivirals, Schecter noted that recent data suggest that the criteria to start antivirals might safely be lower than it has been in the U.S., as one way to minimize the toxicities which may occur in long term use. This is based on information from Dr. Montaner in Canada, who has studied the efficacy of treatment in his patient population in terms of survival. Survival overall was similar when antivirals were initiated in those treated with a CD4 over 200, and no additional benefit could be seen in those who started with a CD4 over 350. However, it must be noted that these data are only studying a few years of observations, and it still may be that there is some advantage to starting treatment at higher CD4 counts that has not yet been demonstrated. Is there any reason to start based on viral load itself, or is this just an indicator of how often to check the CD4 count? This interesting question will be the source of debate for some time to come.
As to the question of what medication to start on, results appear to be similar overall, regardless of the regimen used, particularly with regard to the CD4 response to treatment. However, one study suggests that the pill burden was one key to the success of the regimen, regardless of the class of drugs used. Simplifying regimens has been the focus of drug development for the past few years, including development of treatment options with antiviral combination tablets (e.g., Combivir which is both AZT and 3TC in one tablet, and Trizivir which is AZT, 3TC, and abacavir in one tablet). In addition, there is an increased number of once-daily medication options, including efavirenz (Sustiva) and ddI (Videx).
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